A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H-Related 3 Gene in Atypical Hemolytic Uremic Syndrome

J Am Soc Nephrol. 2016 Jun;27(6):1617-24. doi: 10.1681/ASN.2015010100. Epub 2015 Oct 21.

Abstract

The regulators of complement activation cluster at chromosome 1q32 contains the complement factor H (CFH) and five complement factor H-related (CFHR) genes. This area of the genome arose from several large genomic duplications, and these low-copy repeats can cause genome instability in this region. Genomic disorders affecting these genes have been described in atypical hemolytic uremic syndrome, arising commonly through nonallelic homologous recombination. We describe a novel CFH/CFHR3 hybrid gene secondary to a de novo 6.3-kb deletion that arose through microhomology-mediated end joining rather than nonallelic homologous recombination. We confirmed a transcript from this hybrid gene and showed a secreted protein product that lacks the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a de novo event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise.

Keywords: complement; genetic renal disease; hemolytic uremic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atypical Hemolytic Uremic Syndrome / genetics*
  • Blood Proteins / genetics*
  • Cells, Cultured
  • Complement Activation / genetics*
  • Complement Factor H / genetics
  • Gene Deletion*
  • Humans
  • Sheep

Substances

  • Blood Proteins
  • CFHR3 protein, human
  • complement factor H, human
  • Complement Factor H